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Ichthyoses and related keratinization disorders

The term "ichthyosis" originally comes from the Greek language and is derived from "fish". Therefore the disease named today as ichthyosis is sometimes termed in Germany also "fishlike scaling diseases". However, the German term "Fischschuppenerkrankung/fishlike scaling disease" is better avoided as the scales of those affected by ichthyosis do not really look like the scales of fish. Therefore it is better to use the Latin (medical) term ichthyosis. The first written medical reports about persons suffering from ichthyosis date to the 18th century in the English language. However, ichthyoses are definitely not "new" diseases they belong to human mankind and exist as long as humans exist.

Ichthyoses are a group of rare generalized genetic keratinization disorders. They were grouped together because they have a genetic nature and because of the peculiar scaling affecting the entire skin. Other clinical conditions which belong to this group and are considered as related keratinization disorders refer to more localized keratinization disorders such as those diseases in which palms and soles are affected only (so-called palmoplantar keratosis) or the group of erythrokeratoderma in which large parts of the body show cutaneous inflammation and scaling. These related keratinization disorders are considered today to belong to the same group of diseases as very similar biologic disease mechanisms and similar pathophysiologic alterations can be found in these so-called related keratinization disorders. Altogether these disease groups are uncommon rare diseases. The prevalence is for most of these diseases about 1 in 100.000 inhabitants. Therefore we assume that in Germany about 800 until 1.000 patients are extremely severe affected and have a need for high level clinical care. Milder forms of ichthyosis as for example ichthyosis vulgaris or X-linked recessive ichthyosis the latter having a prevalence of 1 in 4.000 inhabitants do not form a focus of NIRK, in general the handicap and the clinical burden due to these diseases is not as marked and patients can manage better.

Nevertheless patients suffering from these milder forms are of course also welcome and the clinicians involved in the network are certainly willing also to address their problems.

Two main groups of ichthyosis can be distinguish

A further subdivision can be achieved if one asks the question whether only the massive scaling/ichthyosis is present in a certain patient or whether further features such as alterations of the hair, moving disorders or developmental retardations are also present in the patient. Thus all types of ichthyosis can be grouped into four major groups namely

a) vulgar or noncongenital ichthyosis without further features,

b) vulgar or noncongenital ichthyosis with additional features,

c) congenital ichthyosis without associated symptoms,

d) congenital ichthyosis with associated further symptoms.

In particular it is important to distinguish between isolated ichthyosis and related keratinization disorders in which only the skin is affected and to differentiate from these those types of "complex ichthyosis" in which the involvement of the skin is just one of several manifestations of a major underlying disease which then constitutes a syndrome.

The prototype of "isolated ichthyosis" is the group of lamellar ichthyoses. In 35 to 40% of these patients a mutation in the gene encoding the enzyme transglutaminase-1 can be found. This enzyme plays a key role in the formation of the so-called "cornified envelope". The cornified envelope is a membrane that covers as an envelope the cells of the horny layer - these cells are also called corneocytes. The cornified envelope is essential for the attachment of the lipids in the horny layer (stratum corneum) and thus has important roles in stabilizing the stratum corneum, in maintaining its integrity and in preventing the so-called transepidermal water loss. Mutations in the gene for the transglutaminase-1 enzyme result in a deficiency of this enzyme with the consequence of a disturbed assembly of the cornified envelope and of the attachment of the lipids to the corneocytes. Using modern technology such a deficiency in the tranglutaminase-1 enzyme can be monitored and demonstrated on sections of the skin under the microscope. Moreover, several further genetic loci for lamellar ichthyoses have been identified. In the US and in the English speaking literature the term lamellar ichthyosis is often reserved for the very severe types of isolated congenital ichthyoses. In German speaking countries all types of isolated congenital ichthyosis in which no blister formation occurs are grouped under this "umbrella" term.

Mutations in epidermal lipoxygenases - the genes resides on the short arm of chromosome 17 - have been found in about 10% of patients with lamellar ichthyosis. The gene loci for the 2 epidermal lipoxygenase genes (Alox 3) and (Alox 12B) are very close to each other on the short arm of chromosome 17 (17p13.1). They form part of a biochemical pathway. The mechanism how such mutations in lipoxygenase genes result in clinical ichthyosis is not yet fully understood. It is speculated that they affect calcium metabolism. A further gene termed "ichthyin" - the gene for ichthyin maps to chromosome 5a33 was recently identified and may affect the hepoxilin metabolic pathway in which arachidonic acid is transformed to heposilin. A further locus was found in some families in North-Africa having mutations in the lipid transporter gene ABCA12 which resides on the long arm of chromosome 2q33-35. Moreover, further loci one of them on the long arm of chromosome 9 have identified. The gene for the ichthyosis of the 9q34 locus is not yet known, but apparently it is characterized by ultrastructural abnormalities corresponding to what in Germany has sometimes also been called ichthyosis congenita type IV according to ultrastructural criteria.

The group of isolated congenital ichthyoses also comprises the bullous types or blister forming types. In the US nomenclature these types often are referred to as "epidermolytic hyperkeratosis". In Germany the term epidermolytic hyperkerato is more often reserved for a histopathologic finding and not used as a diagnosis. In the German nomenclature epidermolytic types of ichthyosis that are blister forming types of ichthyosis would correspond to bullous erythroderma of the so-called Brocq type (underlying mutations concern keratin-1 or keratin-10), to ichthyosis bullosa of Siemens (underlying mutations concern keratin-2e) the so-called annular epidermolytic ichthyosis (underlying mutation concerns keratin-10) and those keratinization disorders of the palms and soles that are called epidermolytic palmoplantar keratoderma or palmoplantar keratosis of the so-called Unna-Thost-Voerner type. This disease is due to mutations in the keratin-9 gene.

The group of complex ichthyosis or syndromic types of ichthyosis and related keratinization disorders comprises among else the Conradi-Huenermann-Happle syndrome being an X-linked dominant disease featuring congenital ichthyosis, a bone disease named chondrodysplasia punctata, eye changes (cataract) and small stature. The genetic defect of this syndrome can be found in a deficiency of the so-called emopamil binding protein that has a key role in the cholesterol biosynthesis cascade. A further X-linked dominant syndrome is congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD syndrome). This disease is due to mutations in the NSDHL-gene which encodes a 3-beta-hydroxy-steroid dehydrogenase and has also an important role in the biosynthesis of cholesterol within the epidermis. Both the CHILD syndrome and the Conradi-Huenermann-Happle syndrome are being intensively studied by a network project in Marburg.

There are many further types of ichthyosis which becomes clear from the long list of diagnosis in the end.

Key points:

Ichthyoses are a large group of heterogeneous diseases. The individual forms look different, they have different clinical outcomes and quite different disease mechanisms. What they share is that all these diseases are due to mutations in genes that is they all have a genetic disposition. As there is a broad clinical heterogeneity, it is not surprising that also quite different genetic mechanisms can be the cause of the various types of ichthyosis. In quite a number of ichthyosis types the deficient genes are known by now. In the remaining often very rare types these deficient genes are still unknown and are actively sought after.

Brigitte.Willis@ukmuenster.de, 04.05.2010